The long term goal is to understand the patterning and differentiation of specialized cell types and their assembly into functional organs. We wish to understand how genes interact to give tissue specialization, including: 1) The mechanisms by which a broadly used receptor can confer a tissue specific response; 2) The molecular basis of terminal differentiation; and 3) The mechanisms by which the development of two tissues is coordinated during their connection. The nematode C. elegans is used as a model organism because these questions can be studied at the resolution of single cells. We are focusing on a subset of uterine cells because this system permits the genes controlling tissue specificity, terminal differentiation, and tissue connections to be studied within the context of one highly defined system. Development of the two uterine cell types (called utse and uv1) that connect to the vulva and the intermediate precursor cell (called pi) that produces them involves strategies used broadly in the formation of many tissues; induction and pattern formation, a reciprocal cell-cell interaction, and an asymmetric cell division. A major goal is to understand how these processes are integrated during development to reproducibly produce correctly patterned and differentiated cells that always connect to the same cells of the adjacent tissue. Mutants with defects in these processes will be used to identify the genes that control them. The precise nature of the mutant phenotypes will provide insight into the mechanism by which these strategies are coordinated during formation of a mature organ. Cell-cell interactions in the C. elegans uterus provide a unique opportunity to understand how a single receptor used broadly in development can confer a cell-type specific response and mediate different kinds of intercellular signaling. The lin-12 gene, a member of the Notch family of receptors, mediates lateral inhibition during several instances of C. elegans development, but induction only during ventral uterine development (in specification of the pi fate). This project involves molecular characterization of egl-29, a gene required for pi fate specification but not for other lin-12-mediated decisions. Egl-29 may be required for maintenance of the ligand in the signaling cell. Another goal is to identify genes that function in the receiving cell to confer specificity. Activating mutations in human and mouse Notch genes cause cancer in some cell types but not others; thus, understanding the molecular basis of the cell type specific behavior of this receptor family may have important implications for delineating the genetic basis of cancer.